This invention relates to alkyl- and/or halo-substituted dibenzofurans and to substituted dibenzo-p-dioxins and to methods of preparing such compounds. It further relates to the use of the compounds as antiestrogenics and to pharmaceutical compositions containing said compounds.
Antiestrogens are a class of chemicals which inhibit estrogens from eliciting their full response in target tissues. They can be used to explore the mechanisms of action of estrogens and to provide treatment for estrogen-dependent diseases (e.g., tumors). An antiestrogenic compound currently being utilized in the treatment of mammary cancer is tamoxifen. Progesterone and related progestins have also been used extensively to treat mammary cancer in laboratory animals and humans. Numerous other antiestrogens have been disclosed in recent years including inhibitors of aromatase (Bednarski U.S. Pat. No. 4,745,109), antiestrogenic hydrazones (Morgan U.S. Pat. No. 4,732,904) and antiestrogenic benzothiophenes (Jones U.S. Pat. No. 4,418,068).
2,3,7,8-tetrachloridibenzo-p-dioxin (TCDD) is one of the most toxic man-made chemicals. It acts through initial binding to the aryl hydrocarbon (Ah) receptors. Research in the past has focused on the identification and mechanisms of the toxic effects of TCDD in the body and particularly on its induction of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD). Mason et al. Toxicol. 41, 21-31 (1986); Denomme et al. Chem. Biol. Interactions, 57, 175-187 (1986).
Recent studies in several laboratories have reported the activity of TCDD as an antiestrogen in rats, mice and MCF-7 human breast cancer cell lines in culture. For example, TCDD treatment resulted in decreased uterine weights in weanling female C57BL/6 mice and female Long Evans rats and TCDD partially blocked the estrogenic effects of 17.beta.-estradiol on uterine weights. Romkes et al., Toxicol. and Applied Pharm. 87, 306-314 (1987). TCDD also decreased constitutive and 17.beta.-estradiol induced uterine and hepatic estrogen and progesterone receptor levels in the female rat and suppressed the estrogen mediated excretion of tissue plasminogen activator activity in MCF-7 human breast cancer cells in culture. Romkes et al., Toxicol. and Appl. Pharmacol. 92, 368-380 (1988); Gierthy et al., Cancer Research 47, 6198-6203 (1987). Kociba and coworkers reported that after long term feeding studies, TCDD significantly decreased the spontaneous development of mammary and uterine tumors in Female Spraque-Dawley rats. Kociba, Toxicol. and Appl. Pharmacol. 46, 279-303 (1978). However, TCDD is so hepatocarcinogenic that it has not been seriously considered for use as a therapeutic antiestrogenic.
TCDD does not bind to the estrogen receptor and studies suggest, although we do not limit ourselves to this theory, that the antiestrogenic activities of TCDD are mediated through the Ah receptor. Many dibenzo-p-dioxin and dibenzofuran analogs of TCDD also exhibit a binding affinity for the Ah receptor. Recent studies have focused on the identification and mechanism of action of these compounds as TCDD antagonists, particularly in inhibiting TCDD-mediated induction of AHH and EROD in laboratory animals and mammalian cells in culture. (Keys et al., Toxicol. Letters, 31 (1986) 151-158, Astroff et al., Molecular Pharmacol. 33:231-236 (1988).) Studies have particularly focused on 1,3,6,8 and 2,4,6,8-substituted dibenzofurans. The activity of the 2,3,6,8- and 1,3,6,8-substituted dibenzofurans and dibenzo-p-dioxins as Ah receptor agonists (e.g., induction of AHH, thymic atrophy, etc.) was low to non-detectable in most biosystems despite their moderate binding affinity for the Ah receptor.